Understanding Bio-Orthogonal Strain-Driven Sydnone Cycloadditions: Data-Assisted Profiles and the Search for Linear Relationships

TL;DR

This paper explores how strain-driven cycloadditions work in bioorthogonal chemistry, using data to find patterns and improve understanding of reaction mechanisms.

Contribution

The study reveals linear relationships and deviations in strain-driven cycloadditions using phenylsydnone derivatives and a strained cycloalkyne.

Findings

Linear relationships and deviations were identified in strain-driven cycloadditions involving phenylsydnone derivatives.

Accurate activation barriers and rate constants were predicted, highlighting the role of strain release and electronic effects.

The results suggest mesoionic cycloadditions can serve as probes for delocalization-assisted strain release in organic reactions.

Abstract

In the realm of click-type reactions and their application to bioorthogonal chemistry in living organisms, metal-free [3+2] cycloadditions involving mesoionic rings and strained cycloalkynes have gained increasing attention and potentiality in recent years. While there has been a significant accretion of experimental data, biological assays, and assessments of reaction mechanisms, some pieces of the tale are still missing. For instance, which structural and/or stereoelectronic effects are actually interlocked and which remain unplugged. With the advent of data-driven methods, including machine learning simulations, quantitative estimations of relevant observables and their correlations will explore better the chemical space of these transformations. Here we unveil a series of linear relationships, such as Hammett-type correlations, as well as deviations of linearity, using the case study of phenylsydnone (and its 4-aryl-substituted derivatives) with a highly reactive bicyclo[6.1.0]nonyne carbinol. Through accurate estimation of activation barriers and prediction of rate constants, our findings further increase the significance of integrating strain release and electronic effects in organic reactivity. Moreover, such results could pave the way to use mesoionics cycloadditions as probes for measuring the extent of delocalization-assisted strain release, which can be applied to related reactions involving dipoles and strained rings.

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